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Anastasov, N. ; Bonzheim, I.* ; Rudelius, M.* ; Klier, M.* ; Dau, T. ; Angermeier, D. ; Duyster, J.* ; Pittaluga, S.* ; Fend, F.* ; Raffeld, M.* ; Quintanilla-Martinez, L.

C/EBPβ expression in ALK-positive anaplastic large cell lymphomas (ALCL) is required for cell proliferation and is induced by the STAT3 signaling pathway.

Haematologica 95, 760-767 (2010)
Publ. Version/Full Text Volltext DOI PMC
Open Access Gold
Background: ALK+ALCL is characterized by the t(2;5) chromosomal translocation, resulting in the expression of the fusion protein NPM-ALK. Recently, we reported the abnormal expression of the transcription factor C/EBPβ in ALK+ALCL, and demonstrated its dependence on NPM-ALK kinase activity. Design and Methods: In this study, the role of C/EBPβ in proliferation and survival of ALK+ALCL was investigated, as well as, the mechanism of its expression and activity. Highly effective shRNA sequences and/or pharmacological inhibitors were used to abrogate C/EBPβ, STAT3, AKT, ERK1/2 and mTOR expression or activity.. Results: Interference with C/EBPβ expression resulted in a dramatic decrease in cell proliferation in ALK+ALCLs, with a mild induction of apoptosis after 6 days. Downregulation of STAT3 resulted in a marked decrease in C/EBPβ mRNA and protein levels with impairment in cell proliferation and viability, underscoring the important role of these two proteins in ALK-mediated oncogenesis. Additionally, we demonstrated that reduction of ERK1/2 activity led to C/EBPβ Thr235 dephosphorylation and moderate growth retardation. The AKT/mTOR signaling pathway did not have any influence on C/EBPβ expression or C/EBPβ phosphorylation. Conclusions: These findings reveal the convergence of STAT3 and ERK1/2 signaling pathways activated by NPM-ALK, in mediating the regulation of C/EBPβ expression, a transcription factor central to NPM-ALK transformation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Anaplastic Large Cell Lymphoma (ALCL); C/EBPβ; STAT3; RNA interference; cell proliferation; BINDING-PROTEIN-BETA; TYROSINE KINASE; GROWTH-HORMONE; MESSENGER-RNA; CYCLIN D1; TRANSCRIPTION; ACTIVATION; CANCER; TARGET; PHOSPHORYLATION
ISSN (print) / ISBN 0390-6078
e-ISSN 1592-8721
Journal Haematologica - The Hematology Journal
Quellenangaben Volume: 95, Issue: 5, Pages: 760-767 Article Number: , Supplement: ,
Publisher Ferrata Storti Foundation
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
Institute of Radiation Biology (ISB)